Abstract

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A hallmark of neurodegenerative diseases is the accumulation of cytoplasmic protein aggregates in neurons of affected subjects. Among recently identified elements of these aggregates are RNA-binding proteins (RBPs) involved in RNA metabolism and alternative splicing and have in common the presence of low complexity domains (LCD) that are prone to self-assemble and form aggregates. The mechanism of cytoplasmic protein aggregation remains elusive. Stress granules (SGs) that are micrometric RNA-protein assemblies located in the cytoplasm of cells exposed to environmental stress are suspected to play the role of seeds. The review sheds light on the recent experimental results that suggest a link between SGs and cytoplasmic protein aggregates but also propose other routes for the formation of these aggregates.

Purpose of Review

To analyze the potential relationship between cytoplasmic protein aggregates in neurons of affected subjects and stress granules.

Recent Findings

Liquid phase separation explains how protein and RNA could assemble in membraneless compartments, notably SGs. These results highlight the importance of RBPs with LCD in the SG assembly. Maturation of SGs and in particular the dense core is a potential source of insoluble protein aggregates.

Summary

Several lines of evidence linked stress granule dynamics to pathogenic protein aggregates. (i) Proteins that accumulate in cytoplasmic aggregates are also SG components. (ii) Neurons are specifically exposed to stress events due to their high metabolism and long lifespan. (iii) Diseases linked protein mutations affect the SG dynamics. (iv) SG dense core could be a breeding ground for protein aggregates. However, we should also keep in mind that SGs are not the only RNA-protein assembly in the cytoplasm; the RNA transport granules could also play a role in the formation of insoluble protein aggregates.

Notes

Compliance with Ethical Standards

Conflict of Interest

Loic Hamon reports non-financial support from Genopole Evry, during the conduct of the study. Serhii Pankivskyi reports grants from Eiffel program, during the conduct of the study. Anastasiia Samsonova reports grants from MSD France, during the conduct of the study. Ioana Dobra and David Pastre each declare no potential conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

•• Van Treeck B, Parker R. Emerging roles for intermolecular RNA-RNA interactions in RNP assemblies. Cell. 2018;174:791–802. RNA-protein interactions are not alone to drive the assembly of SGs and other RNA-rich granules, we should also take into account the interactions between RNA molecules.CrossRefGoogle Scholar